Pharmacokinetic Study With a Loading Dose of Clofazimine in Adult Patients With Nontuberculous Mycobacterial Disease (C-LOAD)

Clofazimine (CFZ) is a promising drug for the treatment of NTM diseases. CFZ is highly active in vitro against M. abscessus and M. avium, the most common NTM pathogens, and shows synergy with macrolides and amikacin. The results from limited clinical studies with CFZ-based treatment regimens are promising. CFZ is currently considered an alternative drug for patients with M. avium complex infections, who are intolerant of first-line drugs. CFZ is a first-line oral drug for treatment of M. abscessus infections.

CFZ might prove to be a cornerstone in NTM treatment, but its optimal dosage is not known. The current dose for adults is 100 mg oncedaily. However, due to the complex pharmacokinetics (PK) of CFZ - it is highly protein bound, extremely lipophilic and accumulates in fatty tissues resulting in a long elimination half-life of ~30 days - it takes several months before steady state, and presumably effective, concentrations are achieved. With the use of a loading dose regimen concentrations similar to those at steady state could be reached faster, possibly leading to improved early treatment efficacy.

The overarching aim of this study is to contribute to dose optimization of CFZ in the treatment of NTM diseases. It will be an explorative, single-center, one-arm, open label, pharmacokinetic study. A number of 10 patients with pulmonary or extrapulmonary NTM disease will be included. Patients will receive a loading dose regimen of 300 mg once daily for 4 weeks and will then continue with a standard dose of 100 mg once daily until a total 4 months of treatment with CFZ.

The primary objective of this study is to describe the PK of CFZ, after 4 weeks of treatment with a loading dose regimen of 300 mg once daily, in adult patients with pulmonary or extrapulmonary NTM disease

Study Overview

• Status: Completed
• Conditions: Nontuberculous Mycobacterial Diseases
• Intervention / Treatment: Drug: Clofazimine

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2

Contacts and Locations

Study Locations

• Netherlands
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6525 GA
      • Radboud University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• The participant is diagnosed with pulmonary or extrapulmonary NTM disease and is eligible for treatment with CFZ
• The participant is at least 18 years of age
• The participant has a body weight (in light clothing and with no shoes) of at least 45 kg
• The participant is able and willing to provide written, informed consent

Exclusion Criteria:

• The participant is in poor general condition where participation in the study cannot be accepted per discretion of the Investigator
• There is evidence showing the participant has clinically significant metabolic, gastrointestinal, or other abnormalities that could possibly alter the PK of CFZ
• The participant is diagnosed with cystic fibrosis
• The participant has a prolongation of the QTc interval, > 450 milliseconds for males and > 460 milliseconds for females, on the screening ECG
• The participant has abnormal alanine aminotransferase (ALT) and/or aspartate transferase (AST) levels of > 3 times the upper limit of the laboratory reference range at screening
• The participant is pregnant or is using inadequate contraceptive measures (if applicable)
• The participant is breastfeeding (if applicable)
• The participant has a known or suspected, current drug or alcohol abuse, that is, in the opinion of the Investigator, sufficient to compromise the safety or cooperation of the patient
• The participant has as history of allergy/hypersensitivity to CFZ
• The participant has received clofazimine in the past 3 months before inclusion with the exception of short-term use of no more than 7 days in the period of 1 to 3 months before inclusion

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Loading dose Clofazimine; All participants will receive an (experimental) oral loading dose regimen of 300 mg clofazimine (CFZ) once daily (= 3 capsules of 100 mg) for 4 weeks. Afterwards, all participants will continue with a standard oral dose of 100 mg clofazimine once daily (= 1 capsule of 100 mg) until a total 4 months of treatment with CFZ.

Drug: Clofazimine; All participants will receive an (experimental) oral loading dose regimen of 300 mg clofazimine once daily (= 3 capsules of 100 mg) for 4 weeks. Afterwards, all participants will continue with a standard oral dose of 100 mg clofazimine once daily (= 1 capsule of 100 mg) until a total 4 months of treatment with CFZ. Blood samples will be taken at Day 28 (+/- 2 days), Day 29 (Day 28 +1) and after 4 months of treatment to assess the pharmacokinetics of CFZ, both with the loading dose and the standard dose. In addition, the safety/tolerability of CFZ will monitored.; Other Names: Lamprene

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic parameters of clofazimine after a loading dose regimen (1)	The area under the curve (AUC0-24), after a loading dose regimen of 300 mg once daily for 4 weeks in adult patients with pulmonary or extrapulmonary NTM disease.	24 hours sampling at Day 28 (+/- 2 days)
Pharmacokinetic parameters of clofazimine after a loading dose regimen (2)	The peak plasma concentration (Cmax), after a loading dose regimen of 300 mg once daily for 4 weeks in adult patients with pulmonary or extrapulmonary NTM disease.	24 hours sampling at Day 28 (+/- 2 days)
Pharmacokinetic parameters of clofazimine after a loading dose regimen (3)	The plasma trough concentration (Cmin), after a loading dose regimen of 300 mg once daily for 4 weeks in adult patients with pulmonary or extrapulmonary NTM disease.	24 hours sampling at Day 28 (+/- 2 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference between the highest measured concentrations of CFZ in this study and a reference study	Difference between the highest measured concentrations of CFZ in this study and a reference study (PERC study; EudraCT number 2015-003786-28) after approximately 1 and 4 months of treatment.	After approximately 1 and 4 months of treatment
The predicted time (e.g. weeks) needed to reach steady state concentrations with and without a loading dose	Based on the PK parameters in this study and a reference study (PERC study; EudraCT number 2015-003786-28), the time (in weeks or months) that is needed to reach steady concentrations will be predicted. This will be done for both the loading dose regimen and for a standard dose regimen (i.e. the current clinical care). The goal is to assess how much faster steady state concentrations are reached with a loading dose regimen compared to the standard dose.	Expected: 1 to 4 months
Predicted PK parameters (1)	The predicted area under the curve (AUC0-24), after approximately 1 and 4 months of treatment in both this study and a reference study (PERC study; EudraCT number 2015-003786-28)	After approximately 1 and 4 months of treatment
Predicted PK parameters (2)	The predicted peak concentration (Cmax), after approximately 1 and 4 months of treatment in both this study and a reference study (PERC study; EudraCT number 2015-003786-28)	After approximately 1 and 4 months of treatment
Predicted PK parameters (3)	The predicted trough concentration (C0), after approximately 1 and 4 months of treatment in both this study and a reference study (PERC study; EudraCT number 2015-003786-28)	After approximately 1 and 4 months of treatment
Adverse Events	The number of (participants with) adverse events will be measured. Adverse events will be graded according to the 'Common Terminology Criteria for Adverse Events' (CTCAE)	Through study completion, a period of 4 months

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Investigators: Principal Investigator: Prof. dr. R.E. Aarnoutse, PharmD, PhD, Radboud University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): February 14, 2022
• Primary Completion (Actual): May 1, 2023
• Study Completion (Actual): August 8, 2023

Study Registration Dates

• First Submitted: March 1, 2022
• First Submitted That Met QC Criteria: March 15, 2022
• First Posted (Actual): March 24, 2022

Study Record Updates

• Last Update Posted (Actual): August 16, 2023
• Last Update Submitted That Met QC Criteria: August 15, 2023
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: Pulmonary and extrapulmonary NTM diseases
• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Anti-Infective Agents; Anti-Inflammatory Agents; Anti-Bacterial Agents; Leprostatic Agents; Clofazimine
• Other Study ID Numbers: C-LOAD

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No